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Citation: Janjua, O.S.; Shaikh, M.S.;

Fareed, M.A.; Qureshi, S.M.;

Khan, M.I.; Hashem, D.; Zafar, M.S.

Dental and Oral Manifestations of

COVID-19 Related Mucormycosis:

Diagnoses, Management Strategies

and Outcomes. J. Fungi 2022, 8, 44.

https://doi.org/10.3390/jof8010044

Academic Editors: Ana

Fernandez Cruz and Eleni Magira

Received: 10 December 2021

Accepted: 29 December 2021

Published: 31 December 2021

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FungiJournal of

Review

Dental and Oral Manifestations of COVID-19 RelatedMucormycosis: Diagnoses, Management Strategiesand OutcomesOmer Sefvan Janjua 1 , Muhammad Saad Shaikh 2 , Muhammad Amber Fareed 3 , Sana Mehmood Qureshi 4,Muhammad Ikram Khan 5, Danya Hashem 6 and Muhammad Sohail Zafar 6,7,*

1 Department of Maxillofacial Surgery, PMC Dental Institute, Faisalabad Medical University,Faisalabad 38000, Pakistan; [email protected]

2 Department of Oral Biology, Sindh Institute of Oral Health Sciences, Jinnah Sindh Medical University,Karachi 75510, Pakistan; [email protected]

3 Adult Restorative Dentistry, Dental Biomaterials Science and Prosthodontics Oman Dental College,Muscat 116, Oman; [email protected]

4 Department of Oral Pathology, PMC Dental Institute, Faisalabad Medical University,Faisalabad 38000, Pakistan; [email protected]

5 Department of Oral and Maxillofacial Surgery, King Edward Medical University, Lahore 54000, Pakistan;[email protected]

6 Department of Restorative Dentistry, College of Dentistry, Taibah University, Al Madinah,Al Munawwarah 41311, Saudi Arabia; [email protected]

7 Department of Dental Materials, Islamic International Dental College, Riphah International University,Islamabad 44000, Pakistan

* Correspondence: [email protected]; Tel.: +966-507544691

Abstract: It has been nearly two years since the pandemic caused by the novel coronavirus disease(COVID-19) has affected the world. Several innovations and discoveries related to COVID-19 aresurfacing every day and new problems associated with the COVID-19 virus are also coming to light.A similar situation is with the emergence of deep invasive fungal infections associated with severeacute respiratory syndrome 2 (SARS-CoV-2). Recent literature reported the cases of pulmonary andrhino-cerebral fungal infections appearing in patients previously infected by COVID-19. Histopatho-logical analysis of these cases has shown that most of such infections are diagnosed as mucormycosisor aspergillosis. Rhino-orbital-cerebral mucormycosis usually affects the maxillary sinus with in-volvement of maxillary teeth, orbits, and ethmoidal sinuses. Diabetes mellitus is an independent riskfactor for both COVID-19 as well as mucormycosis. At this point, there is scanty data on the subjectand most of the published literature comprises of either case reports or case series with no long-termdata available. The aim of this review paper is to present the characteristics of COVID-19 relatedmucormycosis and associated clinical features, outcome, diagnostic and management strategies. Aprompt diagnosis and aggressive treatment planning can surely benefit these patients.

Keywords: aspergillosis; SARS-CoV-2; mucormycosis; fungal infection; oral mucormycosis

1. Introduction

There is a deep crisis due to the coronavirus disease (COVID-19) pandemic emergingin the last two years and post COVID-19 infection, such as mucormycosis, is addingfurther burden to already strained healthcare systems in some countries. Earlier in 2021,in the midst of the pandemic, COVID-19-related mucormycosis had been reported allaround the world and 70% of those cases were in India in patients with pre-existingconditions or diabetes (94%). COVID-19 patients with diabetic ketoacidosis, cancer, organtransplant, neutropenia, corticosteroid usage, and hemochromatosis were more likely toacquire mucormycosis [1–3].

J. Fungi 2022, 8, 44. https://doi.org/10.3390/jof8010044 https://www.mdpi.com/journal/jof

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Mucormycosis or black fungus is a non-septate filamentous fungal infection that causespotentially life-threatening conditions. This typical infection affects immunocompromisedand diabetic patients most of the time and the symptoms of this deadly infectious conditiondepend on the site of origin, but generally facial structures (nose, sinuses, eye, and brain)are most involved. The symptoms associated with rhino-orbital-cerebral mucormycosis(ROCM) are of varying degree (runny nose, unilateral or bilateral facial swelling, orofacialpain, low to high grade fever, headache, blurred vision due to proptosis and involvementof orbital contents, loosening of teeth, destruction of periodontal tissue and appearance ofblack necrotic eschar or dead bone in the palate, buccal vestibule or the maxillary alveolusalong with formation of oro-nasal/oro-antral communication). Although, in the orofacialand maxillofacial region mucormycosis is very rare especially in healthy, immune com-petent individuals but immune compromised are quite vulnerable to these opportunisticinfections which can involve soft and hard tissues of the facial skeleton necessitating sur-gical intervention and high-dose, long-term parenteral antifungal therapy [4]. A fungigroup of molds known as mucormycetes [5,6] cause mucormycosis, which are spread inour environmental air but is more abundant in soil associated with decaying wood, rottenleaves, compost piles, and animal dung [5,6]. The major route of infection spread is via in-halation, which then involves lungs and paranasal sinuses [7]. Treating COVID-19 patientswith haphazard medication/self-medication of steroids, antibiotics and zinc may havepromoted the dysbiosis of gut microbiota which resulted in inducing immunosuppressionand rapid emergence to this mycotic disease [8,9]. In the present scenario, the highest riskto fungal mucoromycetes infection is in those patients diagnosed and treated for COVID-19with broad-spectrum antibiotics, non-invasive ventilation and received corticosteroid ther-apies. The patients who had pre-existing diseases, such as asthma, diabetes mellitus andchronic renal failure, and developed COVID-19 on top of it are particularly predisposed tocontracting mucormycotic infection.

Although mucormycosis is reported rarely in the localized forms, more recently, sev-eral publications have described the clinical management and outcome of mucormycosis in-fection in the maxillofacial region, for example, the tongue [10], palate [11], mandible [12,13],maxilla [14], and orbitomaxillary/infra-orbital [15,16] region. Therefore, mucormycosisshould be considered as a possible diagnosis in case of any spontaneous soft tissue necroticlesions of orofacial area. In head and neck sites, mucormycosis begins by involving maxil-lary bone or nose and later directly extends to paranasal sinus and from there, spreads toretro-orbital tissues and can disseminate to eye, brain, lungs and to other body organs [17].Therefore, it is crucially important to understand the etiology to make an early diagnosisto provide an optimum treatment of the underlying predisposing factors and appropriatemedical and surgical interventions [15]. This paper discusses some of the important riskfactors, pathophysiology, clinical presentation and outcomes of mucormycosis in patientsinfected with COVID-19, and several therapeutic regimes used for treating mucormycosisare also presented in this review. The recommended Scale for the Assessment of NarrativeReview Articles (SANRA) guidelines [18] were used for reporting this narrative review.Different databases (PubMed and Google Scholar) were searched for the identification ofthe most relevant literature on COVID-19, mucormycosis and fungal infections.

2. COVID-19 and Dentistry

The COVID-19 pandemic has imposed a significant impact on the healthcare system,including dental care practise. COVID-19, caused by the SARS coronavirus 2 (SARS-CoV-2),is presumed to transmit by close contact via respiratory droplets and aerosols. Dentistryis assumed to be involved with the nosocomial transmission of infection due to certainaspects of dental treatment, such as aerosol production and close closeness to patients. Thelikelihood of bidirectional infection transmission between patients and dental care profes-sionals necessitates additional cautious measures to limit the spread of COVID-19. It iscritical to recognize that the rules for delivering dental care during the COVID-19 pandemicwill differ around the globe, and dental clinics should follow their area recommendations.

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This pandemic has also highlighted some of the significant gaps in dental research, as wellas the need for new relevant information to handle the current crisis and reduce the impactof future epidemics on dentistry. To summarize, COVID-19 caused several acute issuesfor dentistry, some of which may have long-term implications for clinical practise, dentaleducation, and dental research [19,20].

In terms of economics, a cross-sectional study was carried out in Nepal and revealedthat a large number of dental practitioners (70 percent) were badly impacted by the financialload and were not paid throughout the lockdown. Only 349 (86%) of dentists believed thatnormal dental treatments should be performed, whereas only 101 (25%) believe that dentalemergency treatments for COVID-19 infected patients should be performed [21].

The influence of COVID-19 on urgent dental treatment at the University HospitalMunich and Bavaria, Germany, was investigated in a research study. Patient numberswithout and with positive/suspected COVID-19 infection, reasons for attendance andtreatments were documented retrospectively and connected to local COVID-19 infectionstatistics, control measures, and numbers/reasons for private dental office closures. Thenumber of patients in the urgent care unit and private dental clinics fell, followed bya complete recovery. While non-emergency visits were essentially non-existent duringthe initial lockdown, pain-related therapies were routinely delivered to individuals withpositive/suspected COVID-19 infections. The most common reasons for practice closureswere a shortage of personal protective equipment (PPE), a lack of personnel, higher healthhazards for staff, and infected staff, accounting for 0.72% of all closures (3.6% closures intotal). Even in times of high infection risk, pain-driven urgent dental treatment remains aconstant requirement, and precautions put in place at the start of the pandemic appear tohave created a safe environment for both patients and oral health care professionals. PPEstorage is critical to ensuring patients’ treatment in high-risk situations, and its storage andadministration by regulatory units may provide a stable and safe oral health care system inthe future [22].

A cross-sectional study carried out in Spain found that the return to work of dentalhygienists entailed several techniques targeted at limiting infection and ensuring the safetyof patients and the rest of the dental team. Personal protective equipment availability,clinical infrastructure adaptability, and patient care management have differed acrossexperts working in the commercial and public sectors [23].

3. COVID-19 Related Fungal Infections (Pulmonary and ROCM)

During the COVID-19 pandemic, the illness has been causing yet another majorhealth catastrophe in India. As of May 2021, the Indian government stated that about12,000 individuals were undergoing treatment for mucormycosis. Many Indian mediasites have dubbed it “black fungus” due to the fungus’s ability to create black staining ofdead and dying tissue. Even before the COVID-19 epidemic, mucormycosis in India wasbelieved to be 70 times greater than the other part of the globe [24,25].

During the COVID-19 pandemic in 2020 and 2021, a number of instances of mucormy-cosis, aspergillosis, and candidiasis were connected to immunosuppressive therapy [26]. Inearly 2021, one review pertaining to the connection between mucormycosis with COVID-19identified eight instances of mucormycosis, three from the United States, two from India,and one each from Brazil, Italy, and the United Kingdom [27]. The BBC reported an upsurgein instances in India in May 2021 [28]. Diabetes was the most frequent underlying medicalcondition [27]. Most patients who were hospitalized with severe respiratory issues causedby COVID-19 had recovered but then acquired mucormycosis within 10 to 14 days. Amongthese patients, five had abnormal kidney function tests, three had sinus, eye, and braininvolvement, three had lung issues, one had gastrointestinal (GI) tract involvement, andone had extensive illness [27]. Mucormycosis was diagnosed during the post-mortem intwo of the seven fatalities. Because none of the three had conventional risk indicators,the authors questioned the use of steroids and immunosuppressive medications [27]. In a

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study of COVID-19-related ocular problems, ophthalmic mucormycosis was discovered tooccur up to several weeks following recovery from COVID-19 [26].

4. Mucormycosis

Baker [29], an American pathologist, created the term mucormycosis in 1957 for asevere Rhizopus infection. Mucormycosis is a rare but deadly fungal illness that oftenaffects people with compromised immune systems. Mucormycosis is an angioinvasiveillness caused by mold fungus of the genera Rhizopus, Mucor, Rhizomucor, Cunninghamella,and Absidia of the Mucorales Order, Class Zygomycetes [30]. The most prevalent variety,Rhizopus oryzae (R. oryzae), is responsible for almost 60% of mucormycosis infections inhumans, as well as 90% of the ROCM variant [31]. The inhalation of fungus spores is themode of contamination.

Mucormycosis is divided into five major kinds based on the area of the body af-flicted [32]. Kidney mucormycosis [33] or mucormycosis affecting at other locations but isless frequent, has been characterized as a sixth kind [32].

� ROCM; prevalent in patients with uncontrolled diabetes or after a kidney trans-plant [34,35].

� Pulmonary; prevalent in cancer patients or those underwent stem cell or organ transplant.� GI; prevalent in premature as well as low-birth-weight infants receiving medicines,

surgery, or drugs that reduce the body’s immune response [36,37].� Burn or other skin damage in patients with leukemia, poorly managed diabetes,

graft-versus-host disease, human immunodeficiency virus (HIV), or intravenous (IV)drug abuse [38].

� Widespread (disseminated), spreads to other body parts through the bloodstream.

4.1. Etiopathogenesis/Pathogenesis

Mucorales may enter the body via contaminated food ingestion, inhalation, or abradedskin regions. It can induce infections in the ROCM, pulmonary, GI, or cutaneous/woundsystems. Mucorales have various characteristics (innate thermotolerance, ability to attachendothelial cell membrane, rapid growth, ability to obtain iron from the host organism,downregulation of host–defense genes associated to pathogen recognition, immune re-sponse, and tissue healing), all of which contribute to the disease’s aggressive nature [39,40].Inhibition of interferon expression [41], as well as an evolutionary duplication of a mech-anism involved in energy consumption and pathogenicity, were discovered in a whole-genome string of R. oryzae [42]. Mucormycosis predisposing factors ketoacidosis anddeferoxamine highlight the role of hyperglycemia, iron, and acidifying ketone bodies inMucorales pathogenicity (Figure 1).

The Mucorales’ virulence factors human pathogens cause illness in the host in twoways: first, infectious bacteria can elude the body’s defense mechanism and survive insidethe host, and second, the immunity is perturbed, impairing the host cells. Pathogen viru-lence factors play an important part in the damage process [43]. Spores inoculate into thehost tissue (depending on the entry site such as alveoli or skin), the evasion of macrophagephagocytosis occurs and they germinating to hyphae (the fungus’s angioinvasive form)thereby increasing their load and attaching to the endothelium via specific unique receptors(spore-coating protein family (CotH)) on the Rhizopus species surface and endotheliumglucose regulator protein (GRP78) [44]. As a result, Rhizopus has an enhanced capacity toinfiltrate host tissues, explaining the vulnerability of diabetic and deferoxamine-treated in-dividuals to mucormycosis. It should be emphasized, however, that the majority of researchon virulence and the relationship between ketoacidosis and the incidence of mucormycosishas been carried out with Rhizopus [45]. Another aspect that contributes to the poorprognosis is Mucorales’ natural resistance to existing antifungals agents (amphotericin B,Posaconazole, itraconazole, and isavuconazole) [46]. Moreover, fungal spores are easilydispersed by aerosolization, local inoculation (e.g., skin lesion), or GI intake. Regardless ofthe source of entrance, the fungus must be established and mucormycosis must develop.

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Mucorales spore germination is known to be inhibited by a decrease in the quantity andfunction of monocytes and neutrophils. Patients with hematological diseases, HIV, or livercirrhosis, as well as those who have had solid organ transplants and are being treated withhigh-dose steroids, fall into this category [46,47].

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Figure 1. Pathogenesis of mucormycosis. β -hydroxybutyrate (BHB); Glucose regulator protein (GPR78); Spore-coating protein family (CotH).

The Mucorales’ virulence factors human pathogens cause illness in the host in two ways: first, infectious bacteria can elude the body’s defense mechanism and survive inside the host, and second, the immunity is perturbed, impairing the host cells. Pathogen viru-lence factors play an important part in the damage process [43]. Spores inoculate into the host tissue (depending on the entry site such as alveoli or skin), the evasion of macrophage phagocytosis occurs and they germinating to hyphae (the fungus’s angioinvasive form) thereby increasing their load and attaching to the endothelium via specific unique recep-tors (spore-coating protein family (CotH)) on the Rhizopus species surface and endothe-lium glucose regulator protein (GRP78) [44]. As a result, Rhizopus has an enhanced ca-pacity to infiltrate host tissues, explaining the vulnerability of diabetic and deferoxamine-treated individuals to mucormycosis. It should be emphasized, however, that the majority of research on virulence and the relationship between ketoacidosis and the incidence of mucormycosis has been carried out with Rhizopus [45]. Another aspect that contributes to the poor prognosis is Mucorales’ natural resistance to existing antifungals agents (am-photericin B, Posaconazole, itraconazole, and isavuconazole) [46]. Moreover, fungal spores are easily dispersed by aerosolization, local inoculation (e.g., skin lesion), or GI intake. Regardless of the source of entrance, the fungus must be established and mu-cormycosis must develop. Mucorales spore germination is known to be inhibited by a decrease in the quantity and function of monocytes and neutrophils. Patients with hema-tological diseases, HIV, or liver cirrhosis, as well as those who have had solid organ trans-plants and are being treated with high-dose steroids, fall into this category [46,47].

4.1.1. Endothelial Interaction Mucorales bind to endothelial cells through the expression of CotH proteins [48]. En-

dothelial cells form the interior layer of blood vessels and play variety of critical roles in pathogen detection and maintaining physiological functions [49], including the ability to phagocytose and destroy Mucorales spores. The receptor GRP78 is found on the endothe-lial cells surface that may detect Mucor species. In the in-vivo research, increasing the glucose and iron content in mice resulted in increased GRP78 expression on the endothe-lial cells surface in multiple organs (sinus, brain, and lungs) than the control [50]. CotH proteins are present exclusively in Mucorales and attach to the host endothelial receptor

GRP78 endothelial surface expression and CotHexpression increase

Fungal growth

Figure 1. Pathogenesis of mucormycosis. β-hydroxybutyrate (BHB); Glucose regulator protein(GPR78); Spore-coating protein family (CotH).

4.1.1. Endothelial Interaction

Mucorales bind to endothelial cells through the expression of CotH proteins [48].Endothelial cells form the interior layer of blood vessels and play variety of critical roles inpathogen detection and maintaining physiological functions [49], including the ability tophagocytose and destroy Mucorales spores. The receptor GRP78 is found on the endothelialcells surface that may detect Mucor species. In the in-vivo research, increasing the glucoseand iron content in mice resulted in increased GRP78 expression on the endothelial cellssurface in multiple organs (sinus, brain, and lungs) than the control [50]. CotH proteinsare present exclusively in Mucorales and attach to the host endothelial receptor GRP78,resulting in fungus endocytosis after endothelial cells are exposed to acidosis and increasediron and glucose levels (hyperglycemia and diabetic ketoacidosis), both GRP78 endothelialsurface expression and CotH fungal surface expression increase [51].

Several clinically relevant observations on the interplay of these receptors are reportedin the literature. Acidosis caused by β-hydroxybutyrate (BHB) (a ketone body represen-tative) and higher blood iron levels were the primary variables that increased expressionof GRP78 and CotH, but lactic acidosis had no effect on their expression. Furthermore,sodium bicarbonate changed the effect and protected BHB–treated mice from mucormyco-sis, suggesting the importance of managing acidosis as a therapeutic strategy in diabeticketoacidosis and mucormycosis [52]. Another study found that either anti-GRP78 oranti-CotH antibodies entirely prevented R. oryzae endothelium invasion [53]. This activity,however, suggests the presence of other components implicated in the interaction betweenendothelial cells and fungus [53]. The development of secondary fungal compounds thatfunction as toxins is another potential cause of endothelium injury [44].

4.1.2. Uptake of Iron

The fact that fungal cells experience apoptosis in low iron circumstances lends credenceto the importance of iron in fungal cell growth [54]. Furthermore, a mouse model of

J. Fungi 2022, 8, 44 6 of 36

mucormycosis, an increased iron concentration promoted fungal growth by decreasingphagocytosis and IFN–production [55]. Mucorales obtain iron from the host via twoprobable methods: high-affinity iron permeases or siderophores [56]. The presence ofheme-oxygenase copies in R. oryzae or genome sequencing point to a third method of ironabsorption from hemoglobin seen in fungus [42].

Deferoxamine, an iron chelator used in people at high risk of iron overload (e.g., patientson renal replacement therapy and those receiving repeated transfusions), makes peoplemore susceptible to mucormycosis [57]. Subsequent research has suggested that ironchelation therapy with deferasirox or deferiprone protects diabetic ketoacidosis mice frommucormycosis and improves survival, while an adjunctive deferasoxinanophen label studyof eight mucormycosis cases showed beneficial results [57]. Nevertheless, a clinical studyin individuals with mucormycosis reported that used supplementary deferasirox treatmentfailed to demonstrate a survival advantage [58]. Mucorales have ferrioxamine receptors(Fob1 and Fob2) that are activated only in the ferrioxamine presence, allowing fungal ironabsorption. Iron absorption from ferrioxamine is energy-dependent due to the action ofreductase, which liberates ferric iron from deferoxamine extracellularly and converts it tosoluble ferrous iron, as well as full intracellular ferrioxamine uptake [58].

FTR1, a high-affinity iron permease, has been proposed to promote intracellular irontransport from heme or ferrioxamine. It is expressed in iron-depleted settings but inhibitedin iron-rich situations [48]. Acidic sera that promoted R. oryzae growth had more accessibleserum iron (69 g/dL versus 13 g/dL for sera not supporting R. oryzae growth). Lastly,induced acidotic circumstances reduced the iron-binding capacity of sera obtained fromhealthy individuals, suggesting that acidosis momentarily impairs transferrin’s ability tobind iron [59].

4.1.3. Interaction between Mucorales and Immune Defense

Evidence on the relationship between the most common organisms resulting in mu-cormycosis and the role of immune cells is summarized as below:

Platelets

Platelets have an essential function in host immunity, which is well established inthe literature [59]. Following the fungi exposure, granules containing pro-inflammatorycytokines and chemokines, including thrombocidins and transforming growth factor-Bwith fungicidal characteristics, are secreted [60]. Membrane-bound molecules (CD154and platelet Toll-like receptors) are expressed, allowing platelet binding and activation ofdifferent cells and their functions:

Endothelial cells stimulate the intracellular adhesion molecule-1 and vascular celladhesion molecule-1 pathways.

Monocytes can be activated or differentiated into macrophages.Dendritic cells stimulate their maturation, whereas B and T lymphocytes stimulate

their activation.Mucorales spores and hyphae promote platelet activation and enhanced aggregation,

clot formation, and platelet consumption, which causes fungal harm by inhibiting hyphaldevelopment [61]. Besides, platelet aggregation to the fungal wall might inhibit fungifrom spreading hematogenously. Furthermore, necrotic regions in organs that do not havefungal development imply thrombotic ischemia, which might be caused by systematicplatelet activation.

Natural Killer (NK) Cells

NK cells are lymphocytic and have a variety of receptors that may detect diseased cellsand block major histocompatibility complex (MHC) that inhibits receptor activation [62].NK cells are a kind of innate immunity having both direct and indirect cytotoxic abilities.Chemokines and cytokines (IFN-, TNF-, and GMCSF) are also secreted by these cells [63].

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However, in-vitro investigations have revealed that R. oryzae has an immunosuppressiveimpact, preventing the release of immune regulatory chemokines from NK cells [64].

T Cells

Antigen-specific T lymphocytes are type of adaptive immunity and a promisingdiagnostic tool for infectious disease control [65]. Mucorales-specific T cells have beenshown to be detected in the majority of mucormycosis patients as compared to otherindividuals who generated the cytokines IFN-, IL-4, IL-10, and IL-17 these cytokines causedMucorales hyphal destruction [65].

T-inactivated cells treated with cytokines IL-2, IL-7, or both, produce more Mucorales-specific T cells and their cytokines IL-5, IL-10, and IL-13, as well as CD4+ T cells thatrecognize particular Mucorales antigens [66].

Figure 1 shows the pathogenesis of mucormycosis, and Figure 2 demonstrates theproposed interaction of diabetes, corticosteroid, and COVID-19 with mucormycosis.

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Figure 2. Association of diabetes, corticosteroid, and COVID-19 with mucormycosis. Reprinted with permission from ref. [67]. Copyright Year (2021) Copyright Owner’s Name (Elsevier). Glucose reg-ulator protein (GPR78); Spore-coating protein family (CotH).

4.2. The Most Common Risk Factors for Mucormycosis Mucormycosis is often an opportunistic infection with particular risk factors; how-

ever, a minor proportion of infections also occur in healthy individuals [1,68]. People at greatest risk of developing invasive disorders have reduced numbers of mononuclear and polymorphonuclear phagocytes, as seen in neutropenia, or disorders that affect the phag-ocyte function, as in hyperglycemia/acidosis or glucocorticoid administration. These fac-tors weaken the immune system and allow fungus to grow and spread, resulting in inva-sive illness (Figure 2). Table 1 lists the important conditions predisposing to mucormyco-sis development. Moreover, Table 2 shows the factors of immunocompetent individuals developing mucormycosis.

Table 1. Critical predisposing factors which increase mucormycosis vulnerability.

Blood Associated Malignancies (Lymphoma, Leukemia and Myeloproliferative Disorders) Uncontrolled diabetes mellitus concurrent with ketoacidosis

High dose corticosteroids/immuno-suppressive drugs for 2–3 weeks Solid organ malignancies

Solid organ transplantation Therapy with Deferoxamine

Metabolic acidosis Hematopoietic stem cell transplantation

Rheumatologic disorders Multiple transfusions Neonatal prematurity

Malnutrition Prophylaxis with voriconazole (breakthrough invasive fungal infections)

Corticosteroids COVID-19 Pre-existing diabetes

↑↑ Cytokines↑ Interleukin-6

↑↑ Ferritin

↑↑ Intracellular free iron

↑↑ Reactive oxygen species

Acute hyperglycemiaNew onset hyperglycemia/diabetes

Diabetic ketoacidosis

HypoxiaLymphopenia

↓ CD4+ and CD8+ T cell

Metabolic acidosis

↑ Endothelial receptor GRP78↑ Mucorales adhesin CotH

Mucormycosis

↑ Ferritin sulphate↓ Iron transport

↑ Ferritin sulphate↓ Iron transport

Figure 2. Association of diabetes, corticosteroid, and COVID-19 with mucormycosis. Reprintedwith permission from ref. [67]. Copyright Year (2021) Copyright Owner’s Name (Elsevier). Glucoseregulator protein (GPR78); Spore-coating protein family (CotH).

4.2. The Most Common Risk Factors for Mucormycosis

Mucormycosis is often an opportunistic infection with particular risk factors; how-ever, a minor proportion of infections also occur in healthy individuals [1,68]. Peopleat greatest risk of developing invasive disorders have reduced numbers of mononuclearand polymorphonuclear phagocytes, as seen in neutropenia, or disorders that affect thephagocyte function, as in hyperglycemia/acidosis or glucocorticoid administration. Thesefactors weaken the immune system and allow fungus to grow and spread, resulting ininvasive illness (Figure 2). Table 1 lists the important conditions predisposing to mucormy-cosis development. Moreover, Table 2 shows the factors of immunocompetent individualsdeveloping mucormycosis.

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4.3. Mucormycosis Clinical Manifestations

The clinical features of mucormycosis vary depending on where the infection islocated. Generally, infection starts in the oral cavity or nose and travels to the centralnervous system through the eyes [38]. If the infection spreads from the sinuses or nose tothe brain, clinical features may involve unilateral eye discomfort or headache, as well asfacial pain, numbness, fever, anosmia, and a runny or blocked nose. The symptoms mayresemble sinusitis individual. One facial side may seem enlarged, with quickly developing“black lesions” through the palate or nose. One of the eyes might appear enlarged andbulging, with blurring of vision, diplopia or decreased visual acuity [69]. When the lungsare affected, symptoms such as pyrexia, chest discomfort, cough, dyspnea, and hemoptysismight develop. When the GI tract is affected, symptoms such as stomach pain, nausea,vomiting, and bleeding may ensue. Due to tissue loss, the skin affected may look like adarkish red sensitive area with a deepening center. There might be an ulcer, which can bequite uncomfortable [38,68,70].

Table 1. Critical predisposing factors which increase mucormycosis vulnerability.

Blood Associated Malignancies (Lymphoma, Leukemia and Myeloproliferative Disorders)

Uncontrolled diabetes mellitus concurrent with ketoacidosis

High dose corticosteroids/immuno-suppressive drugs for 2–3 weeks

Solid organ malignancies

Solid organ transplantation

Therapy with Deferoxamine

Metabolic acidosis

Hematopoietic stem cell transplantation

Rheumatologic disorders

Multiple transfusions

Neonatal prematurity

Malnutrition

Prophylaxis with voriconazole (breakthrough invasive fungal infections)

Table 2. Factors increasing mucormycosis vulnerability in immunocompetent individuals.

Skin injuries, burns, traumaContaminated bandages, tongue depressors.

Combat-related injuriesIntravenous drug abuseProlonged hospital stays

Invasion into blood arteries can cause thrombosis and eventual death of nearby tissueowing to a lack of vascular supply [68]. Because disseminated mucormycosis is oftenpresent in patients with pre-existing medical problems, it may be challenging to determinewhich symptoms are linked to mucormycosis. Patients who have a disseminated mucormy-cosis in the brain may experience changes in the mental status or go into a coma [39,68].One of the initial presentations of ROCM may be multiple mobile teeth with gingivalerythema and pus discharging sinuses. These manifestations mimic odontogenic infectionand has been a source of missed diagnosis by the general dentists who are not familiar withthe clinical presentation of this deadly disease. It has been observed that general dentalpractitioners, who had low index of suspicion for mucormycosis, have wasted precioustime in attempting root canal therapies and performing tooth extractions of these mobileteeth leading to delay the commencement of definitive treatment of mucormycosis andthus resulting in a poor/fatal outcome for the patient [71,72].

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A review by Hussain et al., [73] described the clinical presentation, treatment methods,and patient outcomes of complementary and alternative medicine for COVID-19 associatedmucormycosis. According to this review, diabetes mellitus (73.65%), hypertension (22.75%),and kidney failure (10.77%) were the most frequent co-morbidities among COVID-19associated mucormycosis patients. Moreover, facial discomfort, ptosis, proptosis, visualacuity, and vision loss were the most prevalent complaints identified. Patients who receivedboth medicinal and surgical care had a better chance of survival (64.96%). The overall deathrate among these patients was found to be 38.32%. To decrease morbidity and mortalityassociated with COVID-19 associated mucormycosis, optimal glycemic management andearly detection of mucormycosis should be prioritized [73].

4.4. Mucormycosis Diagnosis

Diagnosis necessitates detecting the mold in the afflicted tissue through biopsy and aconfirmatory fungal culture [56,74]. As the causal fungi are found everywhere, cultivationalone is not sufficient [38]. Culture as well as direct detection of the pathogen in bodyfluids such as blood, serum, plasma, lung fluid, and urine are additional possible tests [75].Complete blood levels are performed as part of the blood tests to look for neutropenia.Levels of blood glucose, iron, bicarbonates, and electrolytes are among the other blood tests.It is possible that an endoscopic evaluation of the nasal passages will be required [3,76].

4.4.1. Clinical Diagnosis

An identification of host variables, quick evaluation of clinical symptoms, and a strongindex of suspicion are required for the diagnosis of mucormycosis. Pleuritic discomfortin a neutropenic patient or diplopia in a diabetic patient are the symptoms of mucormy-cosis infection that prompt the use of diagnostic imaging techniques and the followingcollection of samples for testing by microbiology, histology, and sophisticated molecularmodalities. Mucormycosis is distinguished by tissue necrosis; nevertheless, the presen-tation and syndrome-oriented method to diagnosis is insufficient in terms of specificityand sensitivity. Other funguses, for example, Fusarium or Aspergillus, can cause similarclinical symptoms. Furthermore, in tuberculosis-endemic nations, the two diseases cancoexist, as seen in a diabetic patient [77]. Nonetheless, there are several characteristicsthat should raise the bar for invasive mucormycosis of lungs. These comprise a history ofprevious voriconazole prophylaxis or the appearance of a breakthrough fungal infectionin an immunocompromised individual receiving Aspergillus but not Mucorales-specificmedications [78]. Corzo-Leon et al. devised a method for detecting ROCM in diabetic indi-viduals. The following clinical manifestations must be regarded “red flags” which includesdiplopia, proptosis, sinus discomfort, periorbital edema, cranial nerve palsy, palatal ulcers,and orbital apex syndrome [79].

Since most of the presenting signs and symptoms are not specific for fungal sinusitis, itis recommended that clinicians and dental practitioners should be cautious and vigilant [80],and should maintain a low threshold for referral to an oral and maxillofacial surgeon orotorhinolaryngologist especially if a patient has a history of COVID-19 infection in thepast where he/she was hospitalized and was administered high-dose systemic steroids,broad anti-microbials and mechanical ventilation presents with any of these red-flags signsand symptoms. This can save the life and vital organs, such as eyes, in a patient who haspost-COVID mucormycosis [81].

4.4.2. Microscopic Examination and Culture

The pillars of diagnosing mucormycosis are direct and histopathological microscopy,and cultures of different clinical samples. Direct microscopy of clinical samples, particularlywith optical brighteners, such as Blankophor [82] and Calcofluor [83] White, provides fora quick and plausible mucormycosis diagnosis [84]. Mucorales hyphae are non-septateor pauci-septate, vary in size and have an uneven, ribbon-like manifestation. Fungalelements are clearly visible on periodic acid-Schiff; hematoxylin and eosin sections or

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Grocott-methenamine. Gomori’s silver is used to highlight fungal hyphae and thus analyzegreater detail of morphology [83]. Inflammation, whether neutrophilic or granulomatous,dominates tissue histology; nevertheless, inflammation might not be present in somecases, notably in immunocompromised people [68]. Invasive lesions are distinguishedby angioinvasion and large infarcts. A perineural invasion may be evident when nervestructures are implicated. In comparison to non-neutropenic individuals, neutropenicindividuals have more widespread angioinvasion [82]. Histopathological analysis maynot always provide a clear distinction between Aspergillus or morphologically similarfungus hyphae and Mucorales hyphae. Tissue identification, on the other hand, is a criticaldiagnostic technique as it separates the fungal existence in the material from a culturecontaminant. On the majority of fungal culture medium, such as Sabouraud agar and potatodextrose agar cultured at 25 ◦C to 30 ◦C, all Mucorales grow quickly (3 to 7 days) [85,86].A microaerophilic environment enhances culture yield for some species [87]. Despite thepresence of fungal hyphae in histopathologic examination, cultures are only positive inhalf of the cases [3]. Because hyphae are of friable nature, they can be destroyed duringmanipulation of tissue. Therefore, evasion of excessive tissue homogenization is suggested.

For immunohistochemistry examination, a particular mouse monoclonal anti-Rhizomucor-antibody has been used; nonetheless, this test has formerly been demonstratedto react with other Mucorales and Entomophthorales [88]. In situ hybridization targeting5S and 18S ribosomal RNA sequences [89] is still under research.

4.4.3. Antifungal Susceptibility Testing and Identification of Species

Identification of species is important for a comprehensive epidemiological understand-ing of mucormycosis and can be useful in epidemic investigations. Mucorales may beeasily distinguished from Aspergillus in cultivation. A study revealed that when examinedby persons with experience of fungal identification, morphological characteristics alonemay provide a higher degree of accuracy [90]. Nevertheless, this is challenging and maybe linked to speciation failures [91]. ID32C kit (bio Merieux, Marcy lÉtoile, France) hasbeen successfully used to identify Lichtheimia corymbifera and R. pusillus, and API 50CH(bioMerieux, Marcy-l’Étoile, France) [92] for Mucor species. Both tests failed to differentiateM. circinelloides and M. rouxii. L. ramosa is detected using ID32C and positive melezitoseassimilation [93]. Although matrix-assisted laser desorption/ionization time-of-flight massspectrometry (MALDI-TOF) is a favorable technique, it has not yet been verified for everyMucorale [94]. Additionally, a dependable technique is to use molecular-based tests thatfocus on the internal transcribed spacer region [91].

M. circinelloides has a greater minimum inhibitory concentration (MIC) in contradic-tion of posaconazole, whereas Cunninghamella and Rhizopus have a greater MIC againstamphotericin B [95]. Few Apophysomyces isolates have a greater MIC for amphotericin B [90].The relevance of this information in patient care is unknown, but it needs to beinvestigated further.

4.4.4. Serology

Enzyme-linked immunosorbent assays [96], immunoblots [97], and immunodiffusiontests [98] are being tried with varying degrees of success. An enzyme-linked immunospot(ELISpot) test identified Mucorales specific T lymphocytes in three hematological patientswith invasive mucormycosis [66]. Mucorales-specific T lymphocytes were not seen in anyof the controls. Further research will be conducted on the use of such particular T cells assurrogate diagnostic indicators.

4.4.5. Molecular Assays

Standard polymerase chain reaction (PCR) [99,100], restriction fragment length poly-morphism analyses (RFLP) [101,102], DNA sequencing of specified genes [103,104], andmelt curve analysis of PCR products are examples of molecular-based tests [105]. All of theassays mentioned above can be used to detect or identify Mucorales. The bulk of molecu-

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lar tests focus on the internal transcribed spacer or the 18S rRNA genes [88,90]. Variousinvestigations have been conducted utilizing either formalin-fixed, paraffin-embedded, orfresh tissue samples [88], with varying results. Sensitivity (70–100%) and specificity (notestimated to 100%) varied among investigations, with the main drawback being the smallnumber of individuals investigated. The efficacy of these in-house tests has not been exten-sively researched, and there has been insufficient clinical assessment; therefore, they cannotbe advocated as an individual, single method in routine clinical investigations [88]. Lately,efforts at molecular diagnostics from blood and serum 58–60 have generated encouragingclinical results. When compared to culture, molecular-based diagnosis from serum ledto earlier diagnosis and overall verified culture-proven instances. Molecular-based diag-nostic tests are currently suggested as important add-on tools that supplement traditionaldiagnostic methods [88,91,105].

4.4.6. Imaging

Imaging, such as CT scans of the sinuses and lungs are frequently performed [106].Signs on chest CT scans, comprising cavities, nodules, pleural effusion, halo signs, andwedge-shaped shadows, displaying blood vessels invasion may imply a fungal infection,though not confirming mucormycosis [107]. A reverse halo sign (RHS) in a patient with areduced neutrophil level and blood cancer is strongly suggestive of mucormycosis [107]. CTscan pictures of mucormycosis may be used to differentiate between orbital mucormycosisand orbital cellulitis, although the imaging may appear similar to Aspergillosis [107]. MRImay also be beneficial [26]. MRI with gadolinium contrast is now the method of choicein ROCM.

In recent research that used consecutive thoracic CT scans on leukemic patients withlow neutrophil count, the RHS was seen in 94% of patients during the first seven days of theillness, but other radiographical abnormalities, like numerous nodules, emerged latter. TheRHS presence on CT was a significant indication of pulmonary mucormycosis in the specificcontext of neutropenic leukemic individuals with lung infection [108]. Another researchcompared CT scans from 24 individuals with pulmonary mucormycosis to those from96 patients with invasive Aspergillosis of lungs. The RHS was more prevalent in mucormy-cosis patients (54%) than in Aspergillosis patients (6%), although several airway-invasivecharacteristics, such as clusters of centrilobular nodules, peribronchial consolidations, andbronchial wall thickening, were more common in aspergillosis patients [109]. While thesefindings are not definitive, they might be utilized as a trigger to initiate aggressive diag-nostic laboratory investigations. Positron emission tomography-computed tomography(PET/CT) with [18F]-fluorodeoxyglucose (FDG) is another developing imaging technologythat may ultimately help in the diagnosis and management of mucormycosis [110]. Endo-bronchial ultrasound-guided fine needle aspiration is also a valuable diagnostic techniquewhen it is possible [111].

In ROCM, as mentioned earlier, contrast enhanced MRI is the imaging of choice.Presentation of classic ‘black turbinate’ sign on axial or coronal slices shows fungal rhino-sinusitis. Non-enhancing lesions of the sinus and extra-sinusal tissues are also seen. Angio-invasion and fungal vasculitis present as infarction of internal carotid artery, central arteryof retina, and cerebral arteries. Contrast enhanced scans can show areas of devitalizedtissues in and around the orbits, maxillary, and the ethmoidal sinuses. Similarly cavernoussinus thrombosis can present as non-enhancing lesion on a contrast-enhanced fat-saturatedMR image. Intra-cranial extension can present as a hypointense dural enhancing lesion. Theusual signs, which suggest fungal involvement on a CT scan, include partial or completeopacifications/haziness of one or more of the para-nasal sinuses, appearance of a separationline between healthy and necrotic bone, which can present with mobility of the teeth,sequestrum formation in the maxilla or zygomatic bone, involvement of the orbital contents,soft tissue prominence and effacement of fat in and around pterygopalatine fossa [112,113].

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4.5. Clinical Cases of Mucormycosis

In this section, three cases of mucormycosis are shown in Figures 3–5.

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Figure 3. Coronal slices of CT scan with sinus opacification and sequestrum formation (A) and (B). Axial slices of the contrast enhanced CT scan and show involvement of maxillary sinuses and nasal turbinates (C) and (D). An axial slice of HRCT of chest showing post-COVID fibrosis (E). A clinical picture showing non-healing extraction sockets and necrotic bone in the maxilla, the rest of the teeth present were grade I mobile (F). OPG of the same patient showing sinus involvement, thickening of the lamina dura of the extraction sockets in the anterior maxilla (G).

A B C D

E F G

Figure 3. Coronal slices of CT scan with sinus opacification and sequestrum formation (A) and (B).Axial slices of the contrast enhanced CT scan and show involvement of maxillary sinuses and nasalturbinates (C) and (D). An axial slice of HRCT of chest showing post-COVID fibrosis (E). A clinicalpicture showing non-healing extraction sockets and necrotic bone in the maxilla, the rest of the teethpresent were grade I mobile (F). OPG of the same patient showing sinus involvement, thickening ofthe lamina dura of the extraction sockets in the anterior maxilla (G).

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Figure 4. Picture A, showing exposed necrotic bone in the left posterior maxilla (A). The axial (B) and coronal (C) slices of contrast enhanced CT scan showing bone destruction, sequestrum for-mation, sinus opacification, and involvement of the nasal turbinates.

Figure 5. An edentulous maxilla with an exposed necrotic bone in the palate and draining sinus in the right canine region (A). The axial (B) and coronal (C) slices of contrast enhanced CT scans of the

A

B C

A B C

D E

Figure 4. Picture A, showing exposed necrotic bone in the left posterior maxilla (A). The axial (B) andcoronal (C) slices of contrast enhanced CT scan showing bone destruction, sequestrum formation,sinus opacification, and involvement of the nasal turbinates.

J. Fungi 2022, 8, 44 14 of 37

Figure 4. Picture A, showing exposed necrotic bone in the left posterior maxilla (A). The axial (B) and coronal (C) slices of contrast enhanced CT scan showing bone destruction, sequestrum for-mation, sinus opacification, and involvement of the nasal turbinates.

Figure 5. An edentulous maxilla with an exposed necrotic bone in the palate and draining sinus in the right canine region (A). The axial (B) and coronal (C) slices of contrast enhanced CT scans of the

A

B C

A B C

D E

Figure 5. An edentulous maxilla with an exposed necrotic bone in the palate and draining sinusin the right canine region (A). The axial (B) and coronal (C) slices of contrast enhanced CT scansof the maxilla respectively showing bone destruction, sequestrum formation, involvement of theright turbinate and sinus opacification. Histopathological slides (H&E staining) showing non-septatefungal hyphae consistent with diagnosis of mucormycosis (D,E).

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4.6. Oral and Dental Manifestations

Table 3 demonstrates the oral and dental manifestations of ROCM [114]. Ahmed et al.described a case series of 21 post-COVID-19 people (2 weeks after recovery) with oral mu-cormycosis (11 males (52.4%) and 10 females (47.6%)) with a mean age of (58 ± 12) years.They observed that in COVID-19 individuals, oral signs of mucormycosis are often evidentin the palate and may include varied degrees of mucosal staining, swelling, ulcerations,superficial necrotic regions in the palate, bone exposure, and necrosis with black eschardevelopment. As a result, palatal ulcerations may be the first presenting symptom, prompt-ing the patient to seek treatment from a dentist, who may be the first clinician to identifyan infection, leading to the diagnosis of mucormycosis [115].

Table 3. Oral and dental manifestations of rhino-orbital-cerebral mucormycosis [114].

Dental pain

Mobile teeth

Halitosis (bad breath)

Nasal stuffiness

Nasal discharge with epistaxis, black purulent discharge

Necrotic bone/Sequestrum formation in the palate and maxillary alveolusFormation of Oro-antral/Oro-nasal communications/fistulae

Non-healing extraction sockets with signs similar to alveolar osteitis or chronic osteomyelitis.Trismus due to involvement of muscles of mastication

Para-sinusal pain

Intraoral/Extra oral draining sinuses

Erythema of nasal mucosa

Palatal ulceration

Facial erythema

Black discoloration of skin

Periorbital erythema and edema, cellulitis

Orbital Pain, Ptosis, Diplopia, Vision loss, OphthalmoplegiaHeadache

5. Management of COVID-19 Related Fungal Infections5.1. Prevention of Mucormycosis

It may not be possible to prevent development of deep invasive fungal infections inpredisposed patients, such as uncontrolled diabetics, transplant patients, patients withchronic sinusitis or previous history of mucormycosis, HIV patients or those taking steroidshowever incidence of mucormycosis in COVID-19 patients may be reduced if certainprecautions are undertaken. These may include [116]:

� Promoting personal hygiene, including general hygiene like that of hands and faceas well as the oral hygiene through proper brushing and antiseptic mouth rinses(chlorhexidine 0.2% or betadine)

� Delivery of oxygen should be in a strictly aseptic environment with regular changingof filters and tubes as they can harbor fungus, if contaminated.

� Aggressive management and monitoring of immunocompromised state like in case ofdiabetes, monitoring of blood sugar levels and employing strict control.

� Using steroids very carefully, under strict control and according to recommended guidelines.� Caution in using tocilizumab and other related agents.� Consider prophylactic oral delayed release posaconazole (600 mg day 1, 400 mg 2 to

14 days and 300 mg for 3-months) or isavuconazole (200 mg q8H for 1- to 2-days and200 mg/day for 3-months) [117].

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5.2. Treatment of Mucormycosis

Management of mucormycosis depends on early diagnosis with a clinician possessinga high index of suspicion, optimization of the underlying disease, thorough debridement,and supportive anti-fungal medication. A mainstay of treatment of invasive fungal infec-tions remains surgical debridement supported with anti-fungal drugs, with reversal ofimmune compromised state affecting the final outcome. Medical management compriseof broad spectrum anti-fungal agents and systemic anti-microbials for prevention againstsuperadded bacterial infections [116,118]. Details of medical and surgical treatment areprovided below.

5.2.1. Medical Treatment

Several types of antifungals have demonstrated efficacy in the treatment of mucormy-cosis (Table 4).

Systemic Agents

A. Amphotericin B:Amphotericin B is a polyene antifungal agent. It comes as either amphotericin B de-

oxycholate, also referred to as conventional amphotericin B and newer lipid formulations,which are considered less toxic than the conventional variety [119]. These newer formula-tions include liposomal amphotericin B, amphotericin B lipid complex, and amphotericin Bcholesteryl sulphate complex. The benefit of these lipid formulations is lesser toxicity, betterdrug delivery to the affected sites and allows provision of a higher daily dose [120]. Formany years, Amphotericin B was considered as first line treatment for invasive candidiasis,mucormycosis and aspergillosis however its popularity is somewhat declining with theadvent of new azole derived antifungals because of a broader spectrum of activity and abetter safety profile. In addition to treatment of mucormycosis and aspergillosis, ampho-tericin B is also considered a drug of choice for cerebral cryptococcosis, coccidioidomycosis,Para coccidioidomycosis, disseminated histoplasmosis, severe blastomycosis, and visceralleishmaniasis [121].

Mechanism of Action:The principal sterol in fungal cell membranes is the ergosterol. Amphotericin B

binds to the ergosterol and opens up ion channels leading to increased cell membranepermeability which in turn produces depolarization of the cell, metabolic disturbances, andleakage of small molecules. The end result of this cascade is destruction of fungal cells.Another mechanism of action is the production of oxidative damage to the cells throughcreation of free radicals leading to cell membrane damage. Moreover, amphotericin Bis thought to enhance the phagocytic properties of macrophages, which improves theclearance of fungus from the body [122].

Dosing and Administration:Fungicidal activity is dose dependent and usually lasts for up to 12 h and the normal

dose ranges from 0.7–1 mg/kg/day, which is given slowly over 2 to 4 h as rapid infusioncan result in cardiotoxicity. Risk of nephrotoxicity is enhanced if the doses exceed 1 mg/kg.The patients who present with a risk of nephrotoxicity should be administered 1000 mLof normal saline prior to infusion of amphotericin B. Higher doses can be administered(3 mg/kg/day) in case of liposomal amphotericin B because produces less nephrotoxicityand remains bound to liposomes in circulation. Higher than usual doses (10 mg/kg/day)are associated with severe nephrotoxicity and infusion related events hence should beavoided [123,124].

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Table 4. Summary of medicinal management of mucormycosis.

Drug Name Class of Drug Mechanism of Action Administration Dosage Side Effects/Contraindications/Warnings Role in Mucormycosis

Amphotericin B Polyene Damage to fungal cell bybinding to ergosterol IV

Dose of Amphotericin Bdeoxycholate is

1–1.5 mg/kg/day whiledose of LiposomalAmphotericin B is

5–15 mg/kg/day [68].

Electrolyte disturbancesNephrotoxicity, hepatotoxicity,

neurotoxicity

1st line agent in all cases unlesscontraindicated or not tolerated by

the patient.

Itraconazole Azole

Inhibition conversion oflansosterol to ergosterol

by blocking14-α-demethylase

Capsules, oralsolution and IV 100–200 mg/day

GI disturbancesHypertensionCardiotoxicity

Minimal activity.2nd or 3rd line agent where better

azoles are not available andamphotericin B cannot be used.

posaconazole Azole

Inhibition conversion oflansosterol to ergosterol

by blocking14-α-demethylase

Oral suspension,delayed release

tablet and IV200–300 mg/day

GI disturbancesHepatotoxicityNephrotoxicity

Infusion related reactions

Used as prophylactic agent inmucormycosis prone individuals2nd line agent after amphotericin

B.Useful as salvage therapy.

Isavuconazole Azole

Inhibition conversion oflansosterol to ergosterol

by blocking14-α-demethylase

Oral and IV 200 mg/day

GI disturbancesHepatotoxicity

Prolongs QT intervalSkin rashes

So far, the best azole with efficacycomparable to amphotericin B and

can be used as first line agent.Useful as salvage therapy.

Echinocandins Cell wall inhibitor

Inhibits enzyme1,3-β-D-glucan causing

damage to fungalcell wall

IV 50–70 mg/day Infusion related reactionsHepatotoxicity

Used as combination therapy withamphotericin B.

Deferasirox Chelators Chelates and removesexcess iron IV 40–60 mg/day

Sensorineural deafnessBlindness

Skin eruptionsAnaphylactic reactions

Used in combination withamphotericin B for reducing

iron overload.Considered adjunctive treatment

in mucormycosis.

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Water-solubility of the drug is virtually absent hence it cannot be given per oral orthrough intramuscular (IM) injection. Amphotericin B is a skin irritant hence its topicaluse is not recommended. Amphotericin B produces high concentrations in tissues likeliver, spleen, bone marrow, kidney, and lungs. When administered intravenously, the cere-brospinal fluid (CSF) concentration is around 5% of that in serum hence for the treatmentof fungal infections of the central nervous system, it is recommended that the drug shouldbe given intrathecally [120,121].

Spectrum of Activity:Liposomal amphotericin B is active against Candida species producing invasive can-

didiasis or candidemia, aspergillus and zygomycetes and it is approved for use in manycountries for the management of invasive fungal infections. For many decades, Am-photericin B deoxycholate was considered the gold standard of treatment for invasivefungal infections. Later these lipid-associated formulations were introduced which haveshown a similar degree of efficacy with a better safety profile. Similarly, liposomal ampho-tericin B is more effective in HIV-related disseminated histoplasmosis and cryptococcalmeningitis [125,126].

Adverse Effects and Contraindications:The majority of the toxicity and adverse effects are produced due to interaction of

amphotericin B with cholesterol in human plasma membranes. Common adverse effectsinclude hypokalemia (which can be prevented with concomitant use of steroids), hypomag-nesemia, severe anaphylactic reactions, nephrotoxicity leading to renal failure, and the needfor renal dialysis(which is reversible in most cases), anemia (normochromic/normocytic)and neurotoxicity causing demyelinating encephalopathy. Anaphylactic reaction is an abso-lute contraindication for administrating amphotericin B. Administration of acetaminophen,diphenhydramine, and hydrocortisone prior to administering amphotericin B can reduceinfusion related side effects [127].

Efficacy in mucormycosis:The outcome of the disease is mainly dependent on the dissemination of infection,

cerebral involvement, and ability to debride surgically as surgical debridement remains themainstay of treatment with medications playing only a supporting role. Lanternier et al.treated 40 cases of mucormycosis with surgical debridement along with liposomal Ampho-tericin B and demonstrated an overall response rate of 36% at 4 weeks of treatment with aslight improvement in response to around 45% at the third month of therapy. They reported53% mortality at the 6-month follow-up. Another finding highlighted was that in around63% cases who were treated with liposomal Amphotericin B, these patients presented withan almost two-fold increase in creatinine levels [128].

Rodriguez-Morales et al. recommend that whenever there is suspicion of mucormy-cosis in COVID related patients, the first line of therapy should be high dose liposomalamphotericin B [129]. Later on, the patients can be switched towards isavuconazole orposaconazole for maintenance therapy. According to their recommendation, conventionalamphotericin B should be avoided, if possible, because of high incidence of toxicity howeverin resource limited settings conventional amphotericin B may be the only agent available.Despite aggressive treatment they have reported a mortality rate up to 70%, depending onthe dissemination of disease and organ involvement [129].

It is a general recommendation that kidney function must be monitored when pre-scribing amphotericin B and second line therapies may have to be considered keeping inview the patient’s response to treatment and organ involvement. Alekseyev et al. suggestcombining amphotericin B with echinocandins, such as caspofungin, or with triazoleslike posaconazole/isavuconazole as alternatives in cases who are allergic or intolerant toamphotericin B [130].

According to Spellberg, post-infection survival was almost 83% if the anti-fungal treat-ment with amphotericin B was initiated within 5-days of diagnosis and it drops to almost49% if the treatment is delayed to more than 6-days hence highlighting the significanceof early diagnosis and early initiation of therapy for these patients [68]. Spellberg and

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his colleagues also reported that liposomal amphotericin B is almost twice as potent andeffective as conventional amphotericin B (survival rates 67% and 39%, respectively) [68].

B. Itraconazole:Itraconazole belongs to the group triazole and depicts broad spectrum anti-fungal

activity. Once with in the body, itraconazole is converted to its metabolite hydroxy-itraconazole which in itself possesses anti-fungal properties [131]. It is available bothin the IV and oral formulations with IV showing better efficacy for deep seated fungalinfections [132]. Newer formulations combine a ring of hydroxypropyl-β-cyclodextrin withitraconazole molecule to improve its absorption and bioavailability making them suitablefor a wider range of infections [131].

Mechanism of Action:Its mechanism of action is similar to that of fluconazole as it prevents cell membrane

function in the fungal cells by inhibiting the synthesis of ergosterol. Precisely speaking,it blocks the conversion of lanosterol to ergosterol by interacting with substrate bindingsite of fungal cytochrome P-450. Defective ergosterol leads to increased cell membranepermeability and it also adversely affects membrane-bound enzyme activity [131,132].

Dosing and Administration:Itraconazole is available in the form of capsules, oral solution, and IV formulations.

The drug is lipophilic hence shows variable absorption when administered in capsuleform. However, the absorption from stomach is better if pH of the gastric contents islow, hence it is recommended that it must be taken with food. Its lipophilicity leads tominimal bioavailability in body fluids, such as saliva, CSF, and lacrimal fluid [131]. In bodyorgans, such as skin, lung, liver, and kidney, the drug concentration may increase 20- fold,especially in the skin; therefore, it is most effective in fungal infections of the skin. Thisproperty of the drug is utilized in a pulse regimen [133].

Spectrum of activity:As mentioned above, itraconazole is a broad spectrum anti-fungal agent and has been

used to treat blastomycosis, aspergillosis, histoplasmosis, paracoccidiodomycosis, coccid-ioidomycosis and candidiasis. In addition to its therapeutic indication, use of itraconazolehas also been recommended by fungal prophylaxis in HIV or other immunocompromisedpatients, owing to its safety profile and minimal fungal resistance [132,134]. Itracona-zole has also been approved by the FDA for treatment of superficial fungal infections,such as onychomycosis, vulvo-vaginal, and oro-pharyngeal candidiasis, and some othertopical mycosis.

Adverse effects and contraindications:Reported side effects, including GI disturbances such as gastric discomfort, nausea,

vomiting and diarrhea [135]. Other relatively uncommon but somewhat serious adverseeffects include resistant hypertension in known hypertensive patients, cardiotoxicity lead-ing to a reduction in contractile forces of the heart and decreased ejection fraction andhepatotoxicity causing raised ALT levels [136]. Therefore, it is recommended that liverenzymes must be monitored if the therapy has to continue for more than 1 month. Itsadministration can also lead to fever, joint pain, dysgeusia, pruritis, and headache.

Use of itraconazole is contraindicated in heart failure patients because of its potentialto cause cardiotoxicity. Similarly, likelihood of causing liver damage makes its use unsafein patients with chronic liver disease. Azoles are labelled as teratogenic and possess embry-otoxic effects, hence the use of itraconazole is contraindicated in pregnant patients becauseit can lead to ocular defects in newborns [137].

Administration of itraconazole can lead to drug-drug interactions because of itsmetabolism using CYP 450 pathway in the liver. The common drugs which it can interferewith include terfenadine, astemizole, midazolam, and oral hypoglycemics. 400 mg/dayis generally considered as the upper safe limit of itraconazole, and serious side effects arereported at doses of 600 mg/day [135].

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Efficacy in mucormycosis:Similar to fluconazole, itraconazole also has a limited efficacy against deep fungal

infections caused by mucor species. According to the literature, the efficacy is limited toAbsidia species. Data based on animal and human studies regarding efficacy of itraconazolein mucormycosis is limited, hence it is not recommended to use itraconazole as a singleagent in the treatment of mucormycosis; however, it can be used as a third line agent in caseamphotericin B is contraindicated and posaconazole is unavailable and even in this case,recommendation is to use it as a combination or adjunctive therapy [138]. According toJeong et al., itraconazole capsules as monotherapy can be prescribed for cutaneous diseasein immunocompetent individuals owing to its ability to accumulate in the superficialinfection sites on the skin. Some in-vitro studies have shown promising results whereitraconazole has shown effectiveness against Mucorales but in most animal studies theresults have been somewhat disappointing [139]. Dannaoui et al. studied the efficacy ofitraconazole against different species and genera of zygomycetes and found in vitro MIC(90) for itraconazole to be in the range of 0.03 to 32 mg/L. They found that Absidia speciesdemonstrated better response to itraconazole as compared to Rhizopus [140]. An almostsimilar results for itraconazole were demonstrated by Almyroudis et al. [141]. These drugsare frequently available in a majority of developing countries in Asia and Africa.

C. PosaconazolePosaconazole is a new triazole antifungal agent, which is structurally related to itra-

conazole and is produced when the chlorine in the phenyl ring of itraconazole is replacedwith fluorine. This structural alteration not only enhances its spectrum of activity butalso helps in improving its potency. Depending on the dose and on the target organism,posaconazole can be either fungicidal or fungistatic. It is available in IV and oral formula-tions and is approved for the treatment and prophylaxis of invasive fungal infections andoropharyngeal candidiasis [142,143].

Mechanism of Action:Since posaconazole is structurally an azole, its mechanism of action is similar to

the rest of the azoles whereby it exerts its actions principally through blocking enzymesterol 14α-demethylase in the cytochrome P-450 dependent pathway. This blocking in-hibits ergosterol synthesis in the fungal cell membrane thus causing fungal cell lysis. Itsfungicidal efficacy has been found to be better than itraconazole in regard to treatment ofzygomycetes [144,145].

Dosing and Administration:Posaconazole is available as oral suspension (40 mg/mL), delayed-release tablet

(100 mg) and injectable solution (18 mg/mL ~ 300 mg/16.7 ml vial). Oral suspension isusually prescribed as 200 mg three times a day, tablet and IV infusion are administeredas 300 mg twice on one day followed by 300 mg OD [146]. These doses are for invasiveinfections and 100 mg BD on one day followed by 100 mg OD is generally administered fororo-pharyngeal candidiasis. For infections resistant to fluconazole and itraconazole, thedose is usually increased to 400 mg BD. Posaconazole, when administered as a therapeuticregimen, is continued for 3 to 4 weeks, depending on the response and severity of thedisease. It is recommended that posaconazole be taken with food, nutritional supplementor with a carbonated beverage as acidic environment enhances its absorption from thestomach [147–149].

Spectrum of activity:Posaconazole is highly lipophilic, well absorbed after oral administration, distributed

extensively, and is one of the most potent azoles thus far produced. Owing to its struc-tural differences from fluconazole and itraconazole, posaconazole possesses the abilityto interact with additional domains of the target making it effective in mutated strainsresistant to fluconazole and itraconazole [147]. It has been found to be effective againstCandida species, cryptococcus neoformans, aspergillus species, fusarium and zygomycetes.As mentioned earlier, posaconazole has been approved for the treatment and prophylaxisof invasive aspergillosis, fusariosis, and zygomycosis, including mucormycosis [150]. At a

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dose of 200 mg three times a day, posaconazole has been found to be effective against break-through fungal infections also. Studies have found statistically significant results in patientstreated with posaconazole for invasive fungal infections as compared to itraconazole andfluconazole [145,151].

Adverse effects and contraindications:The most common side effects reported in literature are GI, with diarrhea, nausea, and

vomiting being on top of the list. Oral formulations generally lead to lesser side effectsthan their IV counterpart. There are reports in the literature where IV infusion had tobe discontinued because patients developed significant infusion related problems [152].Headache, thrombocytopenia, fatigue, weight loss, rash, loss of appetite, mucosal inflam-mation, anemia, edema, nausea, vomiting, and dizziness are other reported side effectsrelated to posaconazole therapy [153].

Clinicians should be cautious when prescribing posaconazole to patients with liverfunction abnormalities and liver function tests must be monitored during the course oftreatment. IV formulations should be avoided in patients with moderate to severe renalimpairment (GFR < 50 mL/min). Another thing which must be monitored during thetherapy is the serum electrolytes because posaconazole is known to cause hypokalemiaand hypomagnesemia [145]. It is known to prolong QT interval and may lead to ECGabnormalities and arrhythmias therefore caution is advised when prescribing in cardiacpatients [154]. Likewise, clinicians should keep in mind drug interactions and concomi-tant use of posaconazole with rifabutin, phenytoin, ritonavir, fosamprenavir, benzodi-azepines, calcium channel blockers, digoxin, cimetidine, and ergot alkaloids should be bestavoided [153].

Efficacy in mucormycosis:Posaconazole as an extended spectrum anti-fungal has demonstrated a better efficacy

against mucormycosis as compared to itraconazole. It is used in three different categoriesfor the treatment of mucormycosis: (i) therapeutic, where it is given as a first line agent orwhere amphotericin B is not tolerated, (ii) prophylactic, in cases which are prone to developmucormycosis e.g., transplant patients, HIV patients etc., and (iii) as salvage therapy forde-escalated, refractory and resistant cases [151].

In-vitro studies for mucormycosis reveal that posaconazole appears slightly betterthan itraconazole and significantly better than voriconazole and fluconazole. It has alsoshown survival benefit in animal models [155]. Greenberg et al. have shown clinicalsuccess in 83% of the cases who were treated for mucormycosis [142]. Another study byManesh et al. demonstrated efficacy of posaconazole in ROCM and their results showedcomplete cure in 66.6% of cases and partial response in 16.6% cases. Their study concludedthat posaconazole should be considered a safe and effective alternative for ROCM casesespecially if toxicity prevents use of amphotericin B [156].

It has been depicted that at doses of 200 mg TDS, posaconazole is significantly more ef-fective in treating breakthrough invasive fungal infections as compared to fluconazole [157].So far, large multicenter trials have not been conducted therefore efficacy cannot be de-termined with certainty. A combination of tacrolimus and posaconazole was tested in anin-vitro and in-vivo study by Lewis et al. and their results showed that the combinationresults in synergism with better results than monotherapy with posaconazole [158].

To this point, posaconazole is used as first line agent in cases that are resistant orintolerant to amphotericin B or as a salvage option. It is also recommended as drug ofchoice for prophylaxis against COVID associated mucormycosis in susceptible individu-als [118,159]. Posaconazole has also been used in conjunction with amphotericin B and thiscombination allows reduction in the overall dose of both drugs leading to better tolerabilityand efficacy [160]. The use of posaconazole in ROCM cases has been shown to prevent theneed for orbital exenteration [161].

The success rate of posaconazole salvage therapy as stated by Sipsas et al. wasaround 70% when the drug was administered at the dose of 200 mg QID. In another

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study, 61% patients showed complete a response and 21% showed a partial response whenposaconazole oral suspension was used for four months [159].

D. Isavuconazole:Isavuconazole is a newly developed second generation, extended spectrum. It is

water soluble triazole antifungal drug, which has been showing promising results invarious yeast and mold infections. Isavuconazole is available as a water-soluble pro-drug, isavuconazonium, which is a tetrazolium salt linked to an aminocarboxyl chain. Itsspectrum of activity is broader than other similar azoles and is available for oral and IVuse. Depending on the target species and the dosing, isavuconazole can be fungistatic orfungicidal [162,163].

Mechanism of Action:Similar to other azoles, isavuconazole disrupts the fungal cell membrane by inhibiting

the CYP-450 dependent synthesis of ergosterol through lanosterol 14-demethylase. Fungalcell death follows this disruption. The structure of isavuconazole contains a side arm,which has affinity for fungal CYP51 protein leading to a broader spectrum of fungicidalactivity [162,164].

Dosing and Administration:Isavuconazole is available as oral (100 and 200 mg) and IV formulations. For IV drug,

unlike voriconazole, addition of cyclodextrin is not needed to achieve solubility whicheliminates cyclodextrin related renal toxicity making it a safer alternative to voriconazole.Peak plasma levels are achieved in 1.5 to 3 h after administration and half-life of the drughas been found to be around 56 to 77 h. After metabolism through plasma esterases, it isconverted to the inactive por-drug, isavuconazonium [162,165].

The recommended doses of isavuconazole for treating mucormycosis are 200 mg twicedaily on day one and two followed by 200 mg daily for 1 to 2 weeks or until the infectionimproves [166].

Isavuconazole has remarkable bioavailability and predictable pharmacokinetics. Theabsorption is independent of food and the drug, and is water soluble. Absence of cyclodex-trin make it relatively liver friendly [162].

Spectrum of activity:Various in-vitro, animal based in-vivo; phase III human based clinical trials have

been conducted, which have revealed the spectrum of activity to include Candida species,cryptococcus, geotrichum, tricosporon, saccharomyces, invasive fungal infections caused byaspergillus species, lichtheimia (absidia), mucor species, Rhizopus, fusarium, trichophyton, andsyncephalastrum species [162].

Clinical research has shown that the efficacy of isavuconazole is similar to that ofposaconazole and Voriconazole for treating oro-pharyngeal candidiasis. It has also depictedactivity against fluconazole and amphotericin B resistant Candida infections. In-vitroand animal-based studies have proven the effectiveness of isavuconazole for successfullyclearing infection caused by invasive molds like zygomycetes and aspergillus. Similarly,it has been shown to clear disseminated disease caused by these organisms. In-vitrostudies have shown that isavuconazole is effective against aspergillus terreus, which inmost cases is resistant to amphotericin B. in addition to this, isavuconazole have beenfound to depict in-vitro activity against itraconazole and voriconazole resistant species ofaspergillus lentulus [163].

Isavuconazole can be used for fungal infections of the brain, but clinical data is scarce,and no definite conclusion can be drawn from the cases reported in literature.

Adverse effects and contraindications:In general. Isavuconazole enjoys good tolerability with minimal adverse effects.

Commonly reported side effects include nausea, vomiting, and diarrhea, which normallydo not require treatment discontinuation. Hepatotoxicity is a known side effect for allantifungal medications and the same is true for isavuconazole therefore monitoring ofliver enzymes is recommended. Contrary to posaconazole, it shortens the QT interval,and this shortening is directly related to the dose of the drug being administered. Other

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uncommon side effects can be skin rashes, pedal edema, muscle pain, insomnia, and a fallin blood pressure.

Since isavuconazole is an inducer of the hepatic enzyme, co-administration withketoconazole, rifampin, carbamazepine, ritonavir, barbiturates, sirolimus, tacrolimus, cy-closporine, colchicine, and digoxin should be avoided at all costs [162,164].

Efficacy in mucormycosis:In the US and EU, isavuconazole is approved for the treatment of invasive mucormy-

cosis. Single arm Phase III VITAL trails has shown isavuconazole is effective against mu-cormycosis and the activity is not inferior to amphotericin B, which till date is consideredthe gold standard of treatment care. Itraconazole and voriconazole have limited activityagainst mucormycosis and isavuconazole has shown superior efficacy in comparison tothese azoles [165]. Graves et al. has demonstrated isavuconazole activity against mucormy-cosis to be better than posaconazole when used as salvage therapy for invasive pulmonaryinfection [166]. To this date no randomized control trials have been done therefore it isnot possible to draw a definite conclusion and most of the data available is in the form ofcase reports and case series. Isavuconazole can be administered as prophylactic treatmentfor susceptible cases but can lead to breakthrough fungal infections just like the case withvoriconazole and posaconazole [164]. Isavuconazole has also been used as salvage therapyfor treating invasive mucormycosis in pediatric patients and satisfactory results have beendemonstrated in the case series by Ashkenazi-Hoffnung et al. [167]. Marty et al. reported amortality of 33% in their series when they treated mucormycosis with isavuconazole versus39% for amphotericin B with the conclusion that the efficacy of isavuconazole is similar toamphotericin B for invasive mucormycotic infections [168]. Miceli et al. have reported anoverall response rate of 31.4% for his cases which included both the categories; primaryinfection and salvage cases. They report mortality rate to be higher in refractory cases (43%)as compared to primary infection cases (33.3%) [162].

Keeping all this data and figures under consideration, it can be assumed that isavu-conazole can be an effective alternative to amphotericin B and can be considered as aprimary treatment option for salvage therapy in amphotericin intolerant or resistant cases.

E. EchinocandinsEchinocandins comprise a group of semi-synthetic anti-fungal drugs, which contain

an N-linked acyl lipid side chain of cyclic lipopolypeptides. The three approved drugsincluded in this category are caspofungin, micafungin, and anidulafungin [169].

Mechanism of Action:The mechanism of fungal killing is unique for echinocandins. They non-competitively

inhibit the enzyme formation of 1,3-β-D-glucan which is a principal component in the wallof the fungal cell and is employed in production of glucan. As a result, the fungal cell wallsare damaged leading to anti-fungal action [170,171].

Dosing and Administration:Echinocandins demonstrate poor bioavailability when administered orally therefore

they are not marketed in oral formulation and the only available form is IV [172]. The vialsare available as either 50 mg/vial or 70 mg/vial. For Candida and aspergillus infections,usually a loading dose of 70 mg is given on day 1 followed by 50 mg for the next 14 days;however, it can be continued depending on the response and severity of the disease [173].

Spectrum of activity:As the general description goes, echinocandins are fungicidal for Candida and fungistatic

for invasive fungal infections caused by aspergillus spp. Echinocandins have been found tobe efficacious against amphotericin B and fluconazole resistant Candida [174]. Candidaspecies, such as C. parasilosis and C. guilliermondii, are however found to be resistant toechinocandins [175]. Similarly, virtually no activity is demonstrated against fungi lackingβ-glucan in their cell wall, which is the primary target agent for echinocandins. Theseinclude cryptococcus neoformans, trichosporon, and zygomycetes [176,177].

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Adverse effects and contraindications:The commonly encountered adverse effects are infusion related and include facial

edema, swelling, rash, itching, and fever. They are usually not life threatening and gen-erally do not require discontinuation of the therapy, which can be minimized using anti-histamines. As with other antifungals, echinocandins adversely affect liver function andmonitoring of LFTs is recommended during the course of the treatment especially in caseof caspofungin. Dose should be reduced to half (35 mg) in mild to moderate hepaticinsufficiency. It can be administered safely in renally deranged patients. Echinocandins aregenerally not prescribed in children [178].

Efficacy in mucormycosis:It has been demonstrated through animal and human studies that echinocandins pos-

sess limited activity against zygomycetes and mucormycosis [179]; however, caspofunginshows some activity against Rhizopus oryzae because of presence of a target enzyme. It hasbeen expressed that caspofungin can be used in combination with amphotericin B for asynergistic effect especially in cases of disseminated disease caused by R oryzae [180]. Theauthors showed 50% improvement in survival when then they combined caspofungin andliposomal amphotericin B as compared to amphotericin B alone [181]. The same effect hasbeen shown with combining amphotericin B and micafungin and anidulafungin. However,significant differences in the efficacy among the three different echinocandins have yet tobe proven [182].

A study involving a small number of patients presenting with ROCM showed sig-nificantly improved survival when caspofungin was combined with amphotericin B ascompared with amphotericin B alone [183]. Further multicenter studies with a largernumber of patients are needed to reach a definitive conclusion.

F. Iron Chelators (Deferoxamine and Deferasirox)Deferoxamine and deferasirox belong to a group of medicines referred to as chelators.

They are primarily used in iron and aluminum toxicity and is approved by FDA to treatiron overload in patients requiring frequent transfusion like those of sickle cell disease orthalassemia [184]. Molecularly deferoxamine is a hexadentate, produced by fermentationof Streptomyces piloses and possesses the ability to bind iron in a ratio of 1:1. Deferasiroxis a newer generation of iron chelators, which possess twice the affinity as demonstratedby deferoxamine and can bind iron in a ratio of 2:1. In hemolytic and thalassemic patients,deferasirox demonstrates higher efficacy as compared to deferoxamine [185].

Mechanism of Action:Deferoxamine binds and chelates free iron (non-transferrin bound), hemosiderin and

ferritin. After binding the drug-iron complex is formed known as ferrioxamine, a water-soluble compound, which is then excreted either through bile or urine [186].

Dosing and Administration:Oral absorption of deferoxamine is poor, hence it has to be given parenterally. The

routes available are IM, subcutaneous (SC), IV with SC being the most favored route. A25 G butterfly needle is used for this purpose and abdomen is usually the favored areafor administration. 10% solution of deferoxamine (40–60 mg/kg/day) is infused SC routeover 10 to 12 h through an infusion pump for 4- to 5-days per week. Co-administrationof vitamin C along with deferoxamine enhances its therapeutic efficiency as vitamin Cincreases the concentration of chelatable iron but caution is advised as this can lead to irontoxicity hence clinician needs to balance both issues.

Deferasirox is available in oral suspension, tablet, and granule form and as IV formu-lations. Initial dose is 20 mg/kg/day with a maximum dose of 40 mg/kg/day. Creatinineclearance must be monitored while administering deferasirox [187].

Adverse effects and contraindications:Sensorineural deafness and vision loss are known adverse effects of long term defer-

oxamine therapy. The effects are reversible only if the therapy is discontinued as soon asthey start to appear. In addition to deafness and blindness, other reported side effects in-clude GI disturbance, erythematous lesions on the skin and anaphylactic reactions. Nausea,

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vomiting, gastric discomfort increased serum creatinine, and proteinuria are commonlyreported side effects for deferasirox.

Overall tolerability of the drug is high however the use is contraindicated in knownhypersensitivity cases and in those who have renal disease. Caution is advised when theclinician wishes to prescribe during pregnancy (category C drug) [185,188].

Efficacy in mucormycosis:Mucorales species require free iron for growth and iron chelators, such as deferoxamine

and deferasirox, possess antifungal properties by producing iron starvation. Therefore, itcan be combined with amphotericin B, but renal function must be monitored closely as bothhave the potential of producing nephrotoxicity. Potential benefit has been demonstratedusing triple therapy with amphotericin B, echinocandins and deferoxamine. Deferoxaminehas been reported to promote fungal infection because it increases the free iron in thebody, but this effect has not been seen with deferasirox because of its higher affinity forfree iron. The combination of deferasirox with liposomal amphotericin B has also beenused as salvage therapy with promising results [58,68,189]. However, the possible utilityof adjunctive deferasirox has only been evaluated in small studies with mixed results. Inaddition, deferasirox as an adjunctive agent for mucormycosis has not been adequatelystudied in humans and therefore, it should not be used.

Topical Agents

Generally, there is limited role of topical treatment in deep invasive fungal infec-tions; however, Kontoyiannis et al. have stated that wounds of the patients afflicted withmucormycotic infections can be washed with amphotericin B solution and dressings canbe soaked with amphotericin B before packing inside the defect cavities. This increasesthe contact time between the drug and the diseases site thus enhancing efficacy of thetreatment [118].

5.2.2. Surgical Treatment

Surgical debridement of Mucormycotic lesions is considered to be the mainstay andmust be initiated as early as possible during the course of the treatment. Repeated andaggressive debridement sessions are at times needed to improve survival and to reducechances of disease spread [118].

The surgical treatment of ROCM ranges from turbinectomy to the point of aggressiveremoval of orbital contents and neurosurgical debridement when the disease has involvedthe cranial cavity [190]. The extent of surgery is usually guided by the extent of the disease,which is assessed both clinically as well as radiologically using CT scans and/or theMRIs [130]. A timely and adequately performed surgery significantly improves survivalof such patients; therefore, any patient who is deemed medically fit to undergo surgeryshould be operated upon without any delay [116]. The surgery for ROCM usually involvesa team approach between otorhinolaryngologists, ophthalmologists, oral and maxillofacialsurgeons, plastic surgeons, and neurosurgeons [191].

Turbinectomy

Nasal cavity is usually considered as the portal of entry for the fungus; therefore,involvement of nasal turbinates is a common occurrence. From the nasal mucosa, thefungal hyphae move on to involve adjacent structures [192]. The presence of black coloredturbinates’ on clinical or endoscopic examination and a non-enhancing turbinate on an MRI(referred to as black-turbinate sign) is an important finding in involvement of turbinates’by mucormycosis [193]. Turbinectomy is a surgical procedure which involves removal ofsome or all of the turbinates’, which are small bony structures found inside the nose andare commonly three to four in number [194].

Turbinectomy is usually carried out to relieve chronic nasal congestion, nasal bleedingor to treat sleep apnea and a deviated nasal septum. The surgical approach to removethe inferior turbinate is usually through the nostrils and can be conducted through elec-

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trocautery, microdebrider, radiofrequency or an endoscope. In case of mucormycosis, themiddle meatus, lateral nasal wall, or the ethmoidal sinuses may have to be debrided alongwith removal of the turbinates [193].

Debridement of the Maxillary, Ethmoidal and Frontal SinusesOnce the fungus has gained entry into the nasal cavity, its further course is dictated by

the immune status of the host. In most of the immunocompromised hosts, the next target isthe maxillary sinuses. Involvement of sinuses present with facial pain, paresthesia of theinfraorbital nerve, headache, nasal blockage, nasal bleeding, and/or dental pain [192]. TheCT scan generally shows dense and non-homogenous mass along the nasal cavity withhyperdense opacified masses in the maxillary and/or ethmoidal sinuses. There can bepresence of dead necrotic bone fragments along the anterior, inferior or the posterior wallsof the maxillary sinuses [195].

Once involved, the sinuses require extensive debridement, which can be carried outintraorally through the Caldwell Luc approach, endoscopically using FESS or through thelateral rhinotomy approach [196,197]. When the disease spreads to involve the frontal sinus,the debridement usually requires a Lynch–Howarth incision or the endoscopic approachwhich prevents the external scarring and disfigurement associated with Lynch–Howarthincision [198,199].

The common complications include numbness of the cheek and upper alveolus area,damage to the nasolacrimal duct, sagging of the cheek area if the anterior maxillary wallis removed, recurrence of infection, damage to the roots of the teeth, and facial scarring ifmaxillary sinus debridement is performed through an open approach [200]. Ethmoidectomycan lead to intraorbital hemorrhage due to damage to anterior ethmoidal artery. Damageto extraocular muscles leading to ophthalmoplegia has also been reported after sinussurgery [201].

Maxillectomy/Palatal Resection

If the disease spreads from the maxillary sinus towards the oral cavity, it often causesangioinvasion of the palatal blood vessels leading to thrombosed necrotic black coloredpalate. The necrosis usually spreads towards the alveolus leading to destruction of thebone around the teeth causing tooth mobility and loss. Anterior and posterior spread fromthe sinus mucosa leads to destruction of the anterior and posterior wall of the maxilla,respectively. Involving these walls requires surgical debridement and removal, the extentof which is guided by the involvement of the bone by the fungus [192].

Depending on the involvement and formation of bony sequestrum, the resection canbe inferior/partial maxillectomy, sub-total maxillectomy with sparing of the orbital flooror total maxillectomy with resection of the orbital floor as well. Likewise, if the diseaseis involving both sides of the jaws, the patient may require bilateral debridement, whichcan be accomplished in a single setting or in multiple sessions. The approach for maxillaryand palatal debridement can be either intraoral using a vestibular incision in the buccalsulcus or extra-oral using a Weber–Fergusson incision [190,202]. Use of a frozen section isrecommended in order to ensure complete removal of the dead and devitalized tissue ifplanning for resection in a single setting [203].

Whenever the maxilla along with palate is resected, there is a resultant defect in the oralcavity leading to formation of an oro-nasal/oro-antral communication, which adverselyaffects the patient’s quality of life in terms of mastication and phonation and thereforerequires reconstruction in order to restore the normal functioning of the stomatognathicsystem. The reconstruction of the maxillary defects can be conducted through the fabrica-tion of obturators, which can be tooth/mucosa supported or implant supported [204,205].Zygomatic implants have emerged as a successful entity in such cases [206]. Various au-thors have reported use of osteo-cutaneous free flaps like free fibula flap, radial forearm,and deep circumflex iliac artery flap with successful uptake [203,207].

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Orbital Exenteration

Orbital contents get involved by mucormycosis when the disease spreads superiorlyfrom the maxillary sinus. The other pathway that explains the orbital involvement isthrough the pterygopalatine and infratemporal fossa. The orbital involvement shouldbe suspected if the examination of the eye reveals chemosis and eyelid oedema, cornealnumbness, ophthalmoplegia, pupillary abnormalities, nystagmus and/or loss of visualacuity. Superior orbital fissure syndrome due to thrombosis of superior ophthalmic veinand orbital apex syndrome can also be presenting signs and symptoms depicting severeorbital involvement by the fungus and are considered sinister signs and it is generally notpossible to save a patient’s eye once they appear [208–210].

Orbital exenteration is a procedure involving resection of the whole of the contentsof the orbit, which includes periorbita, eyelids with or without the adjoining skin. Thesurgery is potentially disfiguring and is reserved for cases which show positive findings inthe eyes and are not responsive to the medical management [211,212].

The resultant defect can be reconstructed using split or full thickness skin graft,pedicled myocutaneous flaps utilizing latissimus dorsi, the pectoralis major flap, and thetemporalis muscle flap [212,213]. Reconstruction using free flap usually utilizes rectusabdominus flap, radial forearm free tissue transfer and anterolateral thigh flap [214].

5.3. Complications

Complications can be experienced from the disease itself or from the treatment ofthat disease.

5.3.1. Complications of the Disease

Mucormycosis originating maxillary sinuses in a diabetic patient mostly spreads to therhino-cerebral region whereas patients having a healthy immune status would have mucorlimited to skin or involving the lungs. If there is ROCM, it would involve the paranasalsinuses and maxillary sinus extending to the palate, skin of the cheek and nose area, orbit,brain, and the cranial bones [192]. Angioinvasion is the hallmark of mucormycosis, andformation of intravascular thrombi leads to infarction and necrosis of the involved tissue.When the disease progresses to the cranial cavity, there can be brain infarction or intracranialhemorrhage due to damage to the vessel walls causing a cerebrovascular accident whichcan be fatal for the patient [203]. Formation of brain abscesses, skull base erosions andcavernous sinus thrombosis has also been reported as a complication of mucormycosis.Similarly, extension to the disease involving meninges can lead to development of fungalmeningitis [202].

Extension of the disease to involve the orbital contents can present with ophthalmo-plegia and decreased visual acuity. Complete blindness can ensue if the central artery ofretina gets thrombosed. Ophthalmoplegia is secondary to involvement of cranial nerves III,IV and/or VI. Orbital cellulitis, conjunctival hemorrhage and orbital edema are other signsof orbital involvement by the fungal hyphae. Progressive involvement of the facial andtrigeminal nerve is also a frequent finding with most of the patients complaining of numb-ness in the area of the cheek and the side of the nose [215]. Involvement of the facial/nasalskin, maxillary alveolus, palate, nasal bridge, ethmoidal, sphenoidal, and frontal sinuseshave also been reported in the literature [216].

The disease can extend posteriorly from the maxillary sinuses and nasal cavity toinvolve the infratemporal fossa, pterygopalatine fossa and muscles of mastication lead-ing to development of trismus and decreased mouth opening. From the infratemporaland pterygopalatine fossa disease can easily spread to involve the cranial base and theorbits [192].

5.3.2. Complications of Medical Treatment

Nausea, vomiting, diarrhea, GI disturbances, hepatotoxicity, nephrotoxicity, cardiotox-icity, infusion related complications, facial swelling, rash, sensorineural deafness, loss of

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color vision, headache, fever, loss of appetite, weight loss, electrolyte disturbances, anddevelopment of breakthrough fungal infections are some of the reported complications ofthe various medications used for the treatment of ROCM [217].

5.3.3. Complications of Surgical Treatment

Post-operative complications include difficulty in eating, speaking, and nasal regur-gitation of fluids if there is a palatal defect. If the resection includes orbital exenterationthen blindness would be a post-operative complication too. Difficulty in oral functioningoften leads to an overall low quality of life. Facial, nasal, and oral deformities are knowncomplications of the surgical management of ROCM [218]. These resultant defects requirereconstruction in the form of loco-regional or distant flaps with or without prosthesis fordental and palatal defects [207].

5.4. Prognosis

Prognosis of any disease largely depends upon the extent of spread, the aggressivenessof disease and the time of treatment. The immune status of the patient, particularly thepresence of any hematologic disease, plays an important role. Localized infections inthe case of mucormycosis have a better prognosis while intracranial extension is a poorprognostic indicator. Studies have shown that rhino-cerebral disease in absence of anysystemic illness has 75% survival rate. The survival rate reduces to 20% if there is a systemicdisease along with ROCM [219]. Mucor is considered to have a high mortality rate if orbito-cerebral involvement is seen with pulmonary disease. The prognosis is much better if theorganism has not invaded beyond the sinus before the surgical intervention [220].

Another important prognostic factor is the time at which the disease was diagnosedand treated. Pagano et al. reported mostly patients of mucormycosis died within 12-weeks’time of diagnosis, whereas aspergillosis has a better survival outcome [221]. Chamilos et al.reported mortality rate to jump from 48.6 to 82.9% by delaying the amphotericin B basetherapy for more than 5 days, especially in patients with hematologic malignancies [78].If mucormycosis affected patients receive surgical and medical treatment on time, thereare chances of mortality rate falling down to less than 20% [68]. ROCM can be diagnosedmuch earlier than pulmonary mucormycosis thus ROCM has a better chance of survivalwith early diagnosis and treatment. On the other hand, pulmonary mucormycosis has amortality rate up to 65% as it is difficult to diagnose and mostly occurs in neutropenic pa-tients [222]. Overall reported mortality with all forms of mucormycosis range from 40–80%with survival rates significantly worse in patients with hematological malignancies andorgan transplantation. Similarly, neonatal patients afflicted with mucormycosis show poorprognosis [223]. Cerebral involvement in an immunocompromised patient usually ends upin fatality. The survival in a rapidly progressive disease is reported to be 3 to 6 weeks [203],A follow-up period of at least 36 months is recommended as there is a 13% possibility ofreoccurrence of disease during the 3-year post-operative period [224]. At 5-year follow-up,an overall survival of around 60% has been reported [225].

5.5. Future Directions/Recommendations

Initial signs and symptoms of ROCM may be subtle and patient may present initiallywith nonspecific pain in the maxilla or cheek area or may present with a loose tooth inthe maxilla, which can easily be mistaken for an odontogenic etiology and thus liable toincorrect diagnosis and inappropriate treatment. Dentists, oral and maxillofacial surgeons,otorhinolaryngologists, may be first responders in cases of previously undiagnosed ROCMand if they are not vigilant and cautious, they can miss the diagnosis till it’s very late. It istherefore suggested that thorough history should be obtained and detailed clinical exami-nation should be conducted in patients who present with non-specific pain/pus dischargein the maxillary/facial region or those who have non healing extraction sockets/OAFs afterextraction/osteomyelitis [226].

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The clinicians should be aware of the red flags such as previous history of COVID-19,especially those who were hospitalized and given high flow oxygen therapy along withhigh dose long term steroids; metabolic diseases, such as diabetes especially if uncontrolled;patients taking immunosuppressive treatment for any reason; or patients who may beimmunosuppressed in any other way [227]. The case must be investigated thoroughlyif any of the clinical presenting signs of ROCM are present in a pre-disposed individualfollowed by aggressive surgical management supported medically. It is better to err onthe side of safety rather than waiting and watching. Similarly, it is the job of dentists anddental hygienists to inform pre-disposed individuals about the risks of developing ROCMand importance of maintaining optimal oral hygiene. Likewise, otorhinolaryngologistsshould counsel these patients about maintaining appropriate nasal hygiene. Physicianstreating COVID-19 patients should use steroids judiciously so that incidence of post-COVIDmucormycosis can be minimized as much as possible.

6. Conclusions

There was an increased surge in the incidence of mucormycosis during the secondwave of the COVID-19 pandemic across the globe. This review has presented the clinicalfeatures of mucormycosis generally and its association with COVID-19, which requires amultidisciplinary management approach along with radiological correlation, and pharma-cological and surgical management of mucormycosis involving the oral and dental region.ROCM is an invasive, opportunistic fungal infection that is progressive and has a highmortality rate. Patients with uncontrolled diabetes mellitus, predisposing co-morbidities,and immunocompromised are at higher risk if not treated at an appropriate time. Therefore,it is imperative to predict and treat the causes of ROCM to achieve a favorable outcomeif diagnosed at the earlier stage, resulting in a better prognosis if the organism has notinvaded beyond the sinus before the surgical intervention. There are higher chances ofsurvival if ROCM can be diagnosed early and receive surgical and medical treatmenton time.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

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